Rare predicted loss-of-function and damaging missense variants inCFHR5associate with protection from age-related macular degeneration

ABSTRACT Age-related macular degeneration (AMD) is a leading cause of blindness among older adults worldwide, but treatment options are limited. Prior genetics studies have implicated the CFH locus, which contains CFH and the five CFHR1-5 genes, in AMD. While the CFH gene has been robustly linked with AMD risk, the potential additional role of the five CFHR genes remains unclear, with strong linkage disequilibrium across the locus hindering the identification of individual gene contributions. Investigation of rare coding variants can help to identify causal genes in such regions. We used whole exome sequencing data from 406,952 UK Biobank participants to examine AMD associations with genes at the CFH locus. For each gene, we used burden testing to examine the association of rare (MAF<1%) predicted loss-of-function (pLOF) and predicted-damaging missense variants with AMD. When adjusting for CFH-region variants previously established to independently associate with AMD, we find that CFHR5 rare variant burden significantly associates with decreased risk of AMD (OR=0.75, p=7×10−4), and that this association is primarily driven by pLOF variants. Furthermore, the association of CFHR5 rare variants with AMD protection is estimated as stronger for individuals carrying the CFH Y402H variant, which increases AMD risk (interaction p=0.04). We also identify increased thinning of the outer segment of the photoreceptor layer of the retina to be a strong predictor of AMD and find that CFHR5 rare variant burden significantly associates with increased thickness of this retinal layer (+0.34 SD, p=4×10−4). These findings suggest CFHR5 inhibition as a potential therapeutic approach for AMD. Competing Interest Statement All of the authors are employees and stockholders of Alnylam Pharmaceuticals. Funding Statement All authors are paid employees of Alnylam Pharmaceuticals, and this was the sole funding source for this research. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All data used for this research were from the UK Biobank (UKB) study. The UKB study was approved by the National Health Service National Research Ethics Service and all participants provided written informed consent allowing use of study data for health-related research. The UKB resource is an approved Research Tissue Bank and is registered with the Human Tissue Authority, meaning that researchers who wish to use it are not required to seek separate ethics approval (unless re-contact of participants is required). Information about ethics oversight in the UKB study can be found at https://www.ukbiobank.ac.uk/ethics/. We accessed data from the UKB resource using applications 26041 and 65851. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Individual-level data analyzed in this study are not public due to privacy restrictions but are available to qualified investigators by application to the UK Biobank. All data generated by these analyses are contained in the published article and the supplemental data.